Physiologic evaluation of pressure support ventilation by nasal mask in patients with stable COPD.
We evaluated the physiologic effects of pressure support ventilation by nasal route (NPSV) in eight patients with severe stable COPD and chronic hypercapnia who were randomly submitted to 2-h sessions of NPSV both with a portable ventilator (Respironics BIPAP device) and with a standard ventilator (Bird 6400ST device) at an inspiratory airway pressure of 22 cm H2O. Two sessions with each ventilator were performed using an FIO2 of 0.21 in each patient on two consecutive days. One patient did not tolerate either form of ventilation. Comparison of spontaneous with BIPAP ventilation showed a significant improvement in pH, PaCO2, and PaO2. Ventilatory pattern assessed by a respiratory inductive plethysmograph showed a significant increase in minute ventilation (VE), VT, and Ttot. Integrated surface diaphragmatic EMG activity measured only during BIPAP device ventilation decreased from that measured during spontaneous breathing. Similar changes in blood gases and ventilatory pattern were observed during ventilation by the Bird 6400ST except for VT/Ti ratio, which significantly increased. Comparison of baseline with measurements performed 12 h after the whole cycle of treatment showed a significant increase in pH and VE and a decrease in PaCO2. We conclude that short-term NPSV may be useful in improving respiratory pattern and blood gases in stable COPD patients with chronic hypercapnia.


How Early Stressful Life Experiences Combine With Adolescents' Conjoint Health Risk Trajectories to Influence Cardiometabolic Disease Risk in Young Adulthood.
Research has primarily focused on additive (unique) associations between early stressful life experiences (specifically, socioeconomic adversity and maltreatment) and young adults' cardiometabolic disease risk without considering multiplicative (synergistic) influences. Furthermore, research has not fully considered the varying patterns of health risk trajectories (e.g., substance use, obesogenic-related behaviors, depressive symptoms) across adolescence and the transition to young adulthood that may link earlier stressful experiences and later cardiometabolic disease risk. This study examined heterogeneity in conjoint health risk trajectories from adolescence to the transition to young adulthood and their additive and multiplicative (synergistic) influences with early stressful life experiences on cardiometabolic disease risk in young adulthood using data from the National Longitudinal Study of Adolescent to Adult Health (n = 9,421; 55.6% female) over a period of 13 years. Four distinct conjoint health risk trajectories were identified considering trajectories of substance use behaviors, obesogenic-related behaviors, and depressive symptoms: (a) overall high-risk, (b) behavioral risks, (c) psycho-obesogenic risks, and (d) overall low-risk. Socioeconomic adversity and maltreatment were additively and multiplicatively associated with cardiometabolic disease risk in young adulthood. Individuals with overall high-risk conjoint trajectories averaged higher cardiometabolic disease risk in young adulthood when they were exposed to early socioeconomic adversity. Implications for personalized interventions for individuals who have experienced multiple forms of health risks are discussed.


Prevalence of hypovitaminosis D and its association with comorbidities of childhood obesity.
Our study sought to further delineate the prevalence of hypovitaminosis D and its relationship to comorbidities of childhood obesity. We conducted a retrospective chart review from 155 obese children aged 5 to 19 years who attended the Penn State Children's Hospital Pediatric Multidisciplinary Weight Loss Program from November 2009 through November 2010. We determined the incidence of hypovitaminosis D and examined its association with comorbidities including elevated blood pressure, diabetes, acanthosis nigricans, depression, hyperlipidemia, hyperinsulinemia, and abnormal liver function test results, as well as age, sex, and geographic location. Under the latest Institute of Medicine definitions, vitamin D deficiency (< 20 ng/mL) and insufficiency (20-29 ng/mL) was present in 40% and 38% of children, respectively. The prevalence of vitamin D deficiency was 27.8% in children aged 5 to 9 years, 35.4% in children aged 10 to 14 years, and 50.9% of children aged 15 years or older. Older age, African-American race, winter/spring season, higher insulin level, total number of comorbidities, and polycystic ovary syndrome (in girls) were significantly associated with vitamin D deficiency. African-American race, winter/spring season, hyperinsulinemia, elevated systolic blood pressure, urban location, and total numbers of comorbidities were significantly associated with hypovitaminosis D (< 30 ng/mL). Hypovitaminosis D is associated with several medical comorbidities in obese children. Given the large percentage of children, even in our youngest age group, who are vitamin D deficient, obese children should be considered for routine vitamin D screening.


Control of mycobacteriosis in zebrafish (Danio rerio) mucosally vaccinated with heat-inactivated Mycobacterium bovis.
Mycobacterial infections greatly affect human and animal health worldwide, and vaccines are effective, sustainable and economic interventions for the prevention and control of these infectious diseases. Recent results support the use of zebrafish as a model for studying the pathophysiology of mycobacterial infection and for the development of novel interventions for tuberculosis (TB) control. Recently, we showed that oral immunization with the heat-inactivated M. bovis vaccine (M. bovis IV) protect wild boar against TB, and suggested that this vaccine may controls mycobacterial infection in other species. In this study we evaluated the effect of M. bovis IV on the control of mycobacteriosis in zebrafish mucosally vaccinated by immersion and challenged intraperitoneally with Mycobacterium marinum. The results showed that the M. bovis IV administered by immersion protected zebrafish against mycobacteriosis caused by M. marinum by reduction in mycobacterial infection, the number of mycobacteria per granuloma and the number of granulomas per fish. An IgM antibody response against M. bovis antigens was developed in vaccinated fish. Evidences suggested that the protective mechanism elicited by mucosal vaccination with M. bovis IV in zebrafish was based on the activation of the innate immune response through the C3 pathway. These results support the use of the M. bovis IV administered by immersion for the control of mycobacteriosis in fish.


Substrate recognition domains within extracellular signal-regulated kinase mediate binding and catalytic activation of mitogen-activated protein kinase phosphatase-3.
Mitogen-activated protein (MAP) kinase phosphatase-3 (MKP-3) is a dual specificity phosphatase that inactivates extracellular signal-regulated kinase (ERK) MAP kinases. This reflects tight and specific binding between ERK and the MKP-3 amino terminus with consequent phosphatase activation and dephosphorylation of the bound MAP kinase. We have used a series of p38/ERK chimeric molecules to identify domains within ERK necessary for binding and catalytic activation of MKP-3. These studies demonstrate that ERK kinase subdomains V-XI are necessary and sufficient for binding and catalytic activation of MKP-3. These domains constitute the major COOH-terminal structural lobe of ERK. p38/ERK chimeras possessing these regions display increased sensitivity to inactivation by MKP-3. These data also reveal an overlap between ERK domains interacting with MKP-3 and those known to confer substrate specificity on the ERK MAP kinase. Consistent with this, we show that peptides representing docking sites within the target substrates Elk-1 and p90(rsk) inhibit ERK-dependent activation of MKP-3. In addition, abolition of ERK-dependent phosphatase activation following mutation of a putative kinase interaction motif (KIM) within the MKP-3 NH(2) terminus suggests that key sites of contact for the ERK COOH-terminal structural lobe include residues localized between the Cdc25 homology domains (CH2) found conserved between members of the DSP gene family.


Theory of Mind and psychometric schizotypy.
The extent to which Theory of Mind impairments are a trait associated with schizotypy is unclear. To date, findings have been mixed. We compared two groups of psychometrically identified schizotypes, namely, those characterized by positive schizotypy (perceptual aberrations and magical ideation; n=36) and those characterized by negative schizotypy (social anhedonia; n=30) to a low schizotypy comparison group (n=68) in terms of their Theory of Mind performance. Theory of Mind was assessed in two ways: a composite Hinting Task and the Reading the Mind in the Eyes Test. The groups were also compared in terms of their self-reported levels of referential thinking. Our results indicate that individuals characterized by positive schizotypy show Theory of Mind deficits, as measured by the Hinting Task. The three groups did not differ in terms of the Eyes Test. Referential thinking was significantly associated with the Eyes Test but not the Hinting Task. Overall these findings suggest that different aspects of schizotypy are associated differentially with Theory of Mind deficits. The results also provide further rationale for the inclusion of multiple tasks when attempting to study multifaceted constructs such as Theory of Mind.


Truven Health Analytics MarketScan Databases for Clinical Research in Colon and Rectal Surgery.
The MarketScan databases are a family of administrative claims databases that contain data on inpatient and outpatient claims, outpatient prescription claims, clinical utilization records, and healthcare expenditures. The three main databases available for use are each composed of a convenience sample for one of the following patient populations: (1) patients with employer-based health insurance from contributing employers, (2) Medicare beneficiaries who possess supplemental insurance paid by their employers, and (3) patients with Medicaid in one of eleven participating states. Eleven supplemental databases are available, which are utilized to overcome the limited clinical data available in the core MarketScan databases. There are several limitations to this database, primarily related to the fact that individuals or their family members within two of the core databases mandatorily possess some form of employer-based health insurance, which prevents the dataset from being nationally representative. Nonetheless, this database provides detailed and rigorously maintained claims data to identify healthcare utilization patterns among this cohort of patients.


Robust incident angle calibration of angle-resolved ellipsometry for thin film measurement.
Angle-resolved ellipsometry with back focal plane imaging has been found to be of increasing importance in recent industrial sensing by virtue of its rich information provided at various incident and azimuthal angles. To achieve high sensing accuracy, the incident angles of a back focal plane must be accurately calibrated. For this purpose, a simple and robust incident angle calibration method based on full-field Brewster angle fitting is proposed, without expensive tools or complex operations. With this method, a back focal plane image is first captured from boundary reflectance through a high-numerical-aperture objective. By extracting annular data from the image, radius-dependent ellipsometric parameters $ (\psi,{\Delta)}$ are calculated. At the end, the radii of the back focal plane are mapped to the angle of incidence by using a fitted Brewster angle as the reference. The method is validated by simulation and experiments using a homemade angle-resolved ellipsometer and a commercial spectroscopic ellipsometer. The results show that the proposed method provides a 75% error reduction approximately from generally used methods.


[The molecular heterogeneity of Shigella sonnei lipopolysaccharide based on polyacrylamide gel electrophoretic data].
The molecular heterogeneity of S. sonnei lipopolysaccharide (LPS), reflecting the size of lateral O-specific polysaccharide chains, has been established by the method of electrophoresis in acrylamide gel in the presence of sodium dodecyl sulfate and urea. The dominating components fall into three types, viz. those with 0-3, 10-16 and 35-40 repeating structures, the remaining components being minor ones. The electrophoretic profile of S. sonnei LPS considerably differs from the profiles of Escherichia coli and S. flexneri LPS, but coincides with the LPS profiles of other strains with different virulence. The preparations of LPS obtained by extraction with trichloroacetic acid have the same electrophoretic profiles as LPS obtained by the method of aqueous phenol extraction. The domination of certain molecular variants reflects, seemingly, specific features of the biosynthesis of LPS, characteristic of a given strain. The mechanisms of the preferable synthesis of lateral O-specific chains of the definite size and the importance of the molecular parameters of lateral chains for the biological properties of LPS require further study.


Acute myeloid leukemia: 2012 update on diagnosis, risk stratification, and management.
Acute myeloid leukemia (AML) results from accumulation of abnormal immature cells in the marrow. These cells interfere with normal hematopoiesis can escape into the blood and infiltrate lung and CNS. The most common cause of death is bone marrow failure. It is likely that many different mutations and/or epigenetic aberrations can produce the same disease, with these differences responsible for the very variable response to therapy, which is AML's principal clinical feature. This rests on demonstration that the marrow or blood has >20% blasts of myeloid lineage. Blast lineage is assessed by multiparameter flow cytometry with CD33 and CD13 being surface markers typically expressed by myeloid blasts. It should be realized that clinical/prognostic considerations, not the blast % per se, should be the main factor determining how a patient is treated. Two features determine risk: the probability of treatment-related mortality (TRM) and, more important, even in patients aged >75 with Zubrod performance status 1, the probability of resistance to standard therapy despite not incurring TRM. The chief predictor of resistance is cytogenetics with a monosomal karyotype (MK) denoting the disease is essentially incurable with standard therapy even if followed by a standard allogeneic transplant (HCT). The most common cytogenetic finding is a normal karyotype (NK) and those of such patients with an NPM1 mutation but no FLT3 internal tandem duplication (ITD), or with a CEBPA mutation, have a prognosis similar to that of patients with the most favorable cytogenetics [inv(16) or t(8;21)] (60-70% cure rate). In contrast, NK patients with a FLT3 ITD have only a 30-40% chance of cure even after HCT. Accordingly analyses of NPM1, FLT3, and CEBPA should be part of routine evaluation, much as is cytogenetics. Risk is best assessed considering several variables simultaneously rather than, for example, only age. Patients with inv(16) or t(8;21) or who are NPM1+/FLT3ITD- can receive standard therapy (daunorubicin + cytarabine) and should not receive HCT in first CR. It seems likely that use of a daily daunorubicin dose of 90 mg/m(2) will further improve outcome in these patients. There appears no reason to use doses of cytarabine > 1 g/m(2) (for example, bid × 6 days), as opposed to the more commonly used 3 g/m(2) . Patients with an unfavorable karyotype (particularly MK) are unlikely to benefit from standard therapy (even with dose escalation) and are thus prime candidates for clinical trials of new drugs or new approaches to HCT; the latter should be done in first CR. Patients with intermediate prognoses (for example, NK and NPM and FLT3ITD negative) should also receive HCT in first CR and can plausibly receive either investigational or standard induction therapy, with the same prognostic information about standard therapy leading one patient to choose the standard and another an investigational option.


Theoretical investigation of the formation of a new series of antioxidant depsides from the radiolysis of flavonoid compounds.
This paper deals with the formation of a series of antioxidant depsides obtained from flavonoid solutions irradiated with gamma rays. These reactions take place in radiolyzed alcohol solutions, a medium that is very rich in many different highly reactive species and that hosts specific reactions. We focus on the first step of those reactions, i.e., reactivity of the solute (flavonoid) with the alkoxy radicals CH(3)O(*) and CH(3)CH(2)O(*) formed in methanol and ethanol, respectively, and their carbon-centered isomers: the 1-hydroxy-methyl ((*)CH(2)OH) and the 1-hydroxy-ethyl (CH(3)(*)CHOH) radicals. Among the different flavonoid groups of molecules, only flavonols are transformed. To establish the structure-reactivity relationship that explains why the radiolytic transformation occurs only for those compounds, the process is rationalized theoretically, with Density Functional Theory calculations, taking into account the solvent effects by a Polarizable Continuum Model and a microhydrated environment (one or two water molecules surrounding the active center). The first redox reaction, occurring between the flavonol and the reactive species formed upon irradiation of the solvent, is studied in terms of (1) the O-H bond dissociation enthalpy of each OH group of the flavonoids and (2) electron abstraction from the molecule. We conclude that the reaction, initiated preferentially by the alkoxy radicals, first occurs at the 3-OH group of the flavonol. It is then followed by the formation of a peroxyl radical (after molecular oxygen or superoxide addition). The different cascades of reactions, which lead to the formation of depsides via C-ring opening, are discussed on the basis of the corresponding calculated energetic schemes.


From archaeon to eukaryote: the evolutionary dark ages of the eukaryotic cell.
The evolutionary origin of the eukaryotic cell represents an enigmatic, yet largely incomplete, puzzle. Several mutually incompatible scenarios have been proposed to explain how the eukaryotic domain of life could have emerged. To date, convincing evidence for these scenarios in the form of intermediate stages of the proposed eukaryogenesis trajectories is lacking, presenting the emergence of the complex features of the eukaryotic cell as an evolutionary deus ex machina. However, recent advances in the field of phylogenomics have started to lend support for a model that places a cellular fusion event at the basis of the origin of eukaryotes (symbiogenesis), involving the merger of an as yet unknown archaeal lineage that most probably belongs to the recently proposed 'TACK superphylum' (comprising Thaumarchaeota, Aigarchaeota, Crenarchaeota and Korarchaeota) with an alphaproteobacterium (the protomitochondrion). Interestingly, an increasing number of so-called ESPs (eukaryotic signature proteins) is being discovered in recently sequenced archaeal genomes, indicating that the archaeal ancestor of the eukaryotic cell might have been more eukaryotic in nature than presumed previously, and might, for example, have comprised primitive phagocytotic capabilities. In the present paper, we review the evolutionary transition from archaeon to eukaryote, and propose a new model for the emergence of the eukaryotic cell, the 'PhAT (phagocytosing archaeon theory)', which explains the emergence of the cellular and genomic features of eukaryotes in the light of a transiently complex phagocytosing archaeon.


[Solitary ganglioneuroma of the ileo-cecal valve].
Ganglioneuromas may occur in the small and large intestine as either solitary lesions or, more commonly, as multiple lesions (ganglioneuromatosis). The former are very rare, whereas ganglioneuromatosis may be associated with von Recklinghausen's disease and multiple endocrine neoplasia (MEN) type II B. We described the clinicopathologic features of a case of solitary polypoid ganglioneuroma of the ileocecal valve. The lesion was endoscopically diagnosed in a 27 year old man, with a history of abdominal pain. No association with von Reckling-hausen's disease or MEN was identified. Mutational analysis for RET was negative. Microscopically, the tumor consisted of a proliferation of well differentiated Schwann cells and ganglion cells in the lamina propria. The solitary polipoid ganglioneuroma is invariably benign. It shows no evidence of recurrence after total excision.


PLANETARY SCIENCE: Most-Common Meteorites Find a Home Among the Asteroids.
Meteoriticists have long been puzzled by the fact that the most common meteorites, so-called ordinary chondrites, don't appear to have come from the most common asteroids, the S-types. Last week, however, a group of researchers attending the spring meeting of the American Geophysical Union here announced that the 31-kilometer-long S-type asteroid Eros now being orbited by the NEAR Shoemaker spacecraft is made of the same stuff as ordinary chondrites. That conclusion comes from NEAR Shoemaker's first-ever analysis of the elemental composition of an asteroid.


Knockdown of lncRNA PCAT6 Enhances Radiosensitivity in Triple-Negative Breast Cancer Cells by Regulating miR-185-5p/TPD52 Axis.
Long non-coding RNAs (lncRNAs) have been reported to play essential roles in regulating the radiosensitivity of cancers. Prostate cancer-associated transcript 6 (PCAT6) exerts oncogenic roles in several tumors. However, the roles of PCAT6 and its underlying mechanism in regulating the radiosensitivity of triple-negative breast cancer (TNBC) have not been investigated. The expression levels of PCAT6, microRNA-185-5p (miR-185-5p) and tumor protein D52 (TPD52) were determined by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability, apoptosis and colony formation were assessed by Cell Counting Kit-8 (CCK-8) assay, flow cytometry and colony formation assay, respectively. The interaction between miR-185-5p and PCAT6 or TPD52 was predicted by bioinformatics analysis and verified by dual-luciferase reporter assay. Western blot was carried out to detect the protein level of TPD52. PCAT6 and TPD52 were highly expressed and miR-185-5p was lowly expressed in TNBC tissues and cells, which was associated with an aggressive tumor phenotype in patients, affecting lymph node metastasis and clinical stage. PCAT6 or TPD52 knockdown or miR-185-5p overexpression enhanced the radiosensitivity of TNBC cells via inhibiting proliferation and inducing apoptosis. PCAT6 directly interacted with miR-185-5p and negatively regulated miR-185-5p expression. Moreover, TPD52 was confirmed as a target of miR-185-5p. Besides, PCAT6 regulated the radiosensitivity of TNBC cells through acting as a molecular sponge of miR-185-5p to modulate TPD52 expression. Knockdown of PCAT6 promoted the radiosensitivity of TNBC cells through regulating miR-185-5p/TPD52 axis, providing a vital theoretical basis to improve the radiotherapy efficiency of TNBC.


Associations between urinary glyphosate and diabetes mellitus in the US general adult: a cross-sectional study from NHANES 2013-2016.
Glyphosate-based herbicides (GBHs) are used extensively around the world and have become the leading agrochemicals. However, study about the association between glyphosate exposure and the risk of diabetes mellitus (DM) is scarce. This study used 4 years of NHANES data (2013-2016) to further investigate the association. A total of 2535 participants were enrolled in this cross-sectional study. The baseline information and urinary glyphosate levels in diabetic and non-diabetic groups were compared. Using multivariable logistic regression mode, we explored the association between both the continuous and categorical forms of urinary glyphosate and DM risk. Further subgroup analyses based on categorical covariates were also conducted. Urinary glyphosate levels were 0.42 ng/ml in participants with diabetes and 0.34 ng/ml in participants without diabetes (P < 0.05). As a continuous variable, ln-transformed urinary glyphosate was significantly associated with an increased risk of DM in the most adjusted model (OR 1.28, 95% CI 1.03-1.57). However, the association was not significant in the most adjusted categorical model (P > 0.05).In further subgroup analyses, the associations remained significant in several subgroups. This study provides new evidence that glyphosate exposure was associated with a higher risk of diabetes in the American general adult population.


Hamstring injuries in sprinting - the role of eccentric exercise.
This paper assesses a specific connective tissue insufficiency induced hamstring injury occurring in the late swing/early stance phase of sprinting and jumping activities. A literature review related to hamstring injury demonstrates that eccentric muscle action is capable of producing very high forces within the series elastic component (SEC) of the hamstrings in this phase of sprinting. These high forces have been shown to be related to hamstring injury. The utilization of eccentric exercise training regimens can prevent this injury by strengthening the SEC, resulting in a musculotendinous structure theoretically capable of both generating and withstanding higher eccentric and concentric forces.A clinical approach utilizing an eccentric exercise regimen designed to strengthen the hamstrings in the late swing/early stance phase is outlined. A pilot study investigating the exercise indicates it is a valid method of preventing and rehabilitating the hamstring injury in terms of the positions at risk while sprinting, the angular velocities achieved, and the torques produced. J Orthop Sports Phys Ther 1989;10(9):343-349.


Characterization and identification of weissellicin Y and weissellicin M, novel bacteriocins produced by Weissella hellenica QU 13.
To identify and characterize novel bacteriocins from Weissella hellenica QU 13. Weissella hellenica QU 13, isolated from a barrel used to make Japanese pickles, produced two novel bacteriocins termed weissellicin Y and weissellicin M. The primary structures of weissellicins Y and M were determined, and their molecular masses were determined to be 4925·12 and 4968·40 Da, respectively. Analysis of the DNA sequence encoding the bacteriocins revealed that they were synthesized and secreted without N-terminal extensions such as leader sequences or sec signal peptides. Weissellicin M showed significantly high and characteristic homology with enterocins L50A and L50B, produced by Enterococcus faecium L50, while weissellicin Y showed no homology with any other known bacteriocins. Both bacteriocins showed broad antimicrobial spectra, with especially high antimicrobial activity against species, which contaminate pickles, such as Bacillus coagulans, and weissellicin M showed relatively higher activity than weissellicin Y. Furthermore, the stability of weissellicin M against pH and heat was distinctively higher than that of weissellicin Y. Weissella hellenica QU 13 produced two novel leaderless bacteriocins, weissellicin Y and weissellicin M, and weissellicin M exhibited remarkable potency that could be employed by pickle-producing industry. This study is the first report, which represents a complete identification and characterization of novel leaderless bacteriocins from Weissella genus.


Psychosocial relationship status and quality as predictors of exercise intervention adherence and substance use outcomes: Results from the STRIDE (CTN-0037) study.
Social/intimate relationship status and quality are associated with health-promoting behaviors, while living alone or being isolated are adversely associated with physical and mental health outcomes. Limited work has investigated how particular components of one's social environment - usual living arrangements, satisfaction with those arrangements, and global social and family discord - are related to substance use reduction and intervention adherence. We investigated these questions in 270 individuals receiving study intervention for stimulant abuse/dependence through the multi-site Stimulant Reduction Intervention using Dosed Exercise (CTN-0037) trial. Using mixed effects modeling, results indicated that individuals with baseline social discord used stimulants on more days throughout the intervention period than those without social discord (d=0.39). An interaction between gender, usual living arrangements, and satisfaction with those arrangements indicated that women who lived alone and were dissatisfied with that arrangement reported greater days of stimulant use compared to several other groups (d≥1.46). Finally, individuals who reported usually living with a non-partner over the past three years attended a greater percentage of intervention sessions compared to those usually living with a partner (d=0.34). These results identify sample subgroups with adverse stimulant use and intervention adherence outcomes and suggest areas for future inquiry/intervention.


Identification of a kinetically significant anion binding (KISAB) site in the N-lobe of human serum transferrin.
Human serum transferrin (hTF) binds two ferric iron ions which are delivered to cells in a transferrin receptor (TFR) mediated process. Critical to the delivery of iron to cells is the binding of hTF to the TFR and the efficient release of iron orchestrated by the interaction. Within the endosome, iron release from hTF is also aided by lower pH, the presence of anions, and a chelator yet to be identified. We have recently shown that three of the four residues comprising a loop in the N-lobe (Pro142, Lys144, and Pro145) are critical to the high-affinity interaction of hTF with the TFR. In contrast, Arg143 in this loop does not participate in the binding isotherm. In the current study, the kinetics of iron release from alanine mutants of each of these four residues (placed into both diferric and monoferric N-lobe backgrounds) have been determined +/- the TFR. The R143A mutation greatly retards the rate of iron release from the N-lobe in the absence of the TFR but has considerably less of an effect in its presence. Our data definitively show that Arg143 serves as a kinetically significant anion binding (KISAB) site that is, by definition, sensitive to salt concentration and critical to the conformational change necessary to induce iron release from the N-lobe of hTF (in the absence of the TFR). This is the first identification of an authentic KISAB site in the N-lobe of hTF. The effect of the single R143A mutation on the kinetic profile of iron release provides a dramatic illustration of the dynamic nature of hTF.


An enzyme-responsive and photoactivatable carbon-monoxide releasing molecule for bacterial infection theranostics.
Infections caused by pathogenic bacteria, especially the drug-resistant bacteria, are posing a devastating threat to public health, which underscores the urgent needs for advanced strategies to effectively prevent and treat these intractable issues. Here we report a feasible and effective theranostic platform based on an enzyme-sensitive and photoactivatable carbon monoxide releasing molecule (CORM-Ac) for the successive detection and elimination of bacterial infection. The extracellular bacterial lipase can trigger the excited state intramolecular proton transfer (ESIPT) via elimination of the ester group in CORM-Ac, thus providing a fluorescence switch for an early warning of infection. Subsequently, the potent bactericidal therapy against the model bacterial strains, Staphylococcus aureus (S. aureus) and notorious methicillin-resistant Staphylococcus aureus (MRSA), was readily realized via photoinduced release of CO. In addition, the CORM-Ac and CORM showed good biocompatibility within a wide range of concentrations. The results of an infected animal wound test also demonstrated that the CORM-Ac-loaded gauze was effective in indicating the wound infection and accelerating the wound healing via the photoinduced CO release. The simplicity, functional integration, good biocompatibility and broad adaptability make CORM-Ac very attractive for bacterial theranostic applications.


Predators regulate prey species sorting and spatial distribution in microbial landscapes.
The role of predation in determining the metacommunity assembly model of prey communities is understudied relative to that of interspecific competition among prey. Previous work on metacommunity dynamics of competing species has shown that sorting by habitat patch type and spatial patterning can be affected by disturbances. Microcosms offer a useful model system to test the effect of multi-trophic interactions and disturbance on metacommunity dynamics. Here, we investigated the potential role of predators in enhancing or disrupting sorting and spatial pattern among prey in experimental landscapes. We exposed multi-trophic protist microcosm landscapes with one predator, two competing prey, two patch resource types, and localized dispersal to three disturbance regimes (none, low, and high). Then, we used variation partitioning and spatial clustering analysis to analyse the results. In contrast with previous experiments that did not manipulate predators, we found that patch type did not structure prey communities very well. Instead, we found that it was the distribution of the predator that most strongly predicted the composition of the prey community. The predator impacted species sorting by (1) preferentially consuming one prey, thereby acting as a strong local environmental driver, and by (2) indirectly magnifying the impact of patch food resources on the less preferred prey. The predator also enhanced spatial signal in the prey community because of its limited dispersal. Our results indicate that predators can strongly influence prey species sorting and spatial patterning in metacommunities in ways that would otherwise be attributed to stochastic effects, such as dispersal limitation or demographic drift. Therefore, whenever possible, predators should be explicitly included as separate explanatory factors in variation partitioning analyses.


Venous thromboembolism prophylaxis in the medical patient: controversies and perspectives.
Despite the high morbidity and mortality associated with venous thromboembolism in hospitalized at-risk medical patients, the publication of large-scale studies showing that prophylaxis is effective in this patient group, and the presence of international guidelines, prophylaxis rates in medically ill patients remain suboptimal. Studies show that low-molecular-weight heparins, given once daily, are at least as effective as unfractionated heparin usually given thrice daily with equivalent or improved safety profiles, and that thrice-daily dosing of unfractionated heparin might be more effective than twice-daily dosing. However, the most recent American College of Chest Physicians guidelines do not distinguish between these regimens, and twice-daily unfractionated heparin is still commonly used in the United States. Furthermore, the optimal duration for out-of-hospital and extended prophylaxis for specific patient groups is not established. Finally, there are few data on the use of mechanical methods in this patient group and no established standard of care for prophylaxis of special patient populations, such as obese patients or those with renal insufficiency. Even though prophylaxis entails additional acquisition costs, it can reduce the incidence of venous thromboembolism, which can improve care and decrease overall costs.


Epsilon-aminocaproic acid promotes the release of alpha2-antiplasmin during and after cardiopulmonary bypass.
This double-blind, randomized study compared the mechanisms by which low-dose aprotinin and epsilon-aminocaproic acid (EACA) inhibited fibrinolysis during cardiopulmonary bypass surgery. D-dimer levels during and after bypass were similar, indicating an equivalent inhibition of fibrinolysis. Effects on tissue plasminogen activator release were not associated with the inhibition of fibrinolysis by either drug. Treatment with EACA was associated with a substantial release of endogenous alpha2-antiplasmin, particularly 1 h after bypass. Compared with the aprotinin group, higher levels of the plasmin-alpha2-antiplasmin complex in the EACA group confirmed an increased inhibition of plasmin by alpha2-antiplasmin. In conclusion, it is hypothesized that EACA inhibited fibrinolysis by stimulating the release of the patients' own alpha2-antiplasmin.


[Hospital infection and rational antibacterial therapy in conduction of operative interventions in cardiac surgery].
The results of bacteriological monitoring in intensive care units of ICVS AMS of Ukraine, specializing on the treatment of patients after conduction of operation on "open heart", were analyzed. In 1998-2001 yrs the S. Epidermidis and Enterobacter strains had constituted the most frequent causes of septic state in patients. Experience of application of different antibacterial preparations was summarized, the main principles of their administration were formulated. Modern approaches to the treatment and prophylaxis of purulent-septic complications were depicted.


(-)-Epigallocatechin-3-gallate reverses the expression of various tumor-suppressor genes by inhibiting DNA methyltransferases and histone deacetylases in human cervical cancer cells.
There has been increasing evidence that numerous bioactive dietary agents can hamper the process of carcinogenesis by targeting epigenetic alterations including DNA methylation. This therapeutic approach is considered as a significant goal for cancer therapy due to the reversible nature of epigenetic-mediated gene silencing and warrants further attention. One such dietary agent, green tea catechin, (-)-epigallocatechin-3-gallate (EGCG) has been shown to modulate many cancer-related pathways. Thus, the present study was designed to investigate the role of EGCG as an epigenetic modifier in HeLa cells. DNA methyltransferase (DNMT) and histone deacetylase (HDAC) inhibition assays were conducted, and the transcription levels of DNMT3B and HDAC1 were assessed by enzymatic activity assay and RT-PCR, respectively. Furthermore, we studied the binding interaction of EGCG with DNMT3B and HDAC1 by molecular modeling as well as promoter DNA methylation and expression of retinoic acid receptor-β (RARβ), cadherin 1 (CDH1) and death-associated protein kinase-1 (DAPK1) in EGCG-treated HeLa cells by RT-PCR and MS-PCR. In the present study, time-dependent EGCG-treated HeLa cells were found to have a significant reduction in the enzymatic activity of DNMT and HDAC. However, the expression of DNMT3B was significantly decreased in a time-dependent manner whereas there was no significant change in HDAC1 expression. Molecular modeling data also supported the EGCG-mediated DNMT3B and HDAC1 activity inhibition. Furthermore, time-dependent exposure to EGCG resulted in reactivation of known tumor-suppressor genes (TSGs) in HeLa cells due to marked changes in the methylation of the promoter regions of these genes. Overall, the present study suggests that EGCG may have a significant impact on the development of novel epigenetic-based therapy.


Roman digit naming: evidence for a semantic route.
Earlier research with monolinguals and bilinguals showed that numbers may be named through both a semantic and a phonological route, depending on the number's language and format (Arabic or verbal), task demands, and naming language. The present study investigated the importance of the semantic route for the processing of a third representation of magnitude, namely Roman digits. Using an interference paradigm, we showed that the processing of Roman target digits is influenced by Arabic digit distractors, both in a naming task and a parity judgment task. Roman digits were processed faster if the target and distractor were of the same magnitude. If this was not the case, processing speed slowed down as the numerical distance between target and distractor increased. This strongly suggests that semantic access is mandatory when naming Roman digits. Implications are discussed for the number processing domain and for models of translation in bilinguals.


Molecular Epidemiology of G6PD Genotypes in Different Ethnic Groups Residing in Saharan and Sahelian Zones of Mauritania.
Plasmodium vivax malaria is endemic in Mauritania. Individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency may develop acute hemolytic anemia when exposed to 8-aminoquinoline antimalarial drugs, which are indispensable for a complete cure. The prevalence of G6PD allelic variants was assessed in different ethno-linguistic groups present in Mauritania. A total of 996 blood samples (447 males and 549 females; 499 white Moors and 497 individuals of black African ancestry) were collected from febrile patients in 6 different study sites: Aleg, Atar, Kiffa, Kobeni, Nouakchott, and Rosso. The presence of the African-type G6PD A- (G202A, A376G, A542T, G680T, and T968C mutations) and the Mediterranean-type G6PD B- (C563T) variants was assessed by PCR followed by restriction fragment length polymorphism and/or DNA sequencing. The prevalence of African-type G6PD A- genotype was 3.6% (36/996), with 6.3% (28/447) of hemizygote (A-) males and 1.5% (8/549) of homozygous (A-A-) females. Forty of 549 (7.3%) women were heterozygous (AA-). The following genotypes were observed among hemizygous men and/or homozygous women: A376G/G202A (22/996; 2.2%), A376G/T968C Betica-Selma (12/996; 1.2%), and A376G/A542T Santamaria (2/996; 0.2%). The Mediterranean-type G6PD B- genotype was not observed. The prevalence rates of G6PD A- genotype in male (10/243; 4.1%) and heterozygous female (6/256; 2.3%) white Moors were lower (p < 0.05) than those of males (18/204; 8.8%) and heterozygous females (34/293; 11.6%) of black African ancestry. There were only a few homozygous women among both white Moors (3/256; 1.2%) and those of black African ancestry (5/293; 1.7%). The prevalence of G6PD deficiency in Mauritania was comparable to that of neighboring countries in the Maghreb. Because of the purportedly close ethnic ties between the Mauritanian white Moors and the peoples in the Maghreb, further investigations on the possible existence of the Mediterranean-type allele are required. Moreover, a surveillance system of G6PD phenotype and/or genotype screening is warranted to establish and monitor a population-based prevalence of G6PD deficiency.


The role of online social networking on deliberate self-harm and suicidality in adolescents: A systematized review of literature.
Social media use by minors has significantly increased and has been linked to depression and suicidality. Simultaneously, age-adjusted suicide rates have steadily increased over the past decade in the United States with suicide being the second most common cause of death in youth. Hence, the increase in suicide rate parallels the simultaneous increase in social media use. In addition, the rate of nonsuicidal self-injury ranges between 14% and 21% among young people. Evidence suggests that self-harming youth is more active on online social networks than youth who do not engage in self-harm behavior. The role of online social networking on deliberates self-harm and suicidality in adolescents with a focus on negative influence was assessed by conducting a systematized literature review. A literature search on "PubMed" and "Ovid Medline" using a combination of MeSH terms yielded nine articles for data extraction satisfying predefined inclusion/exclusion criteria. It was found that social networking websites are utilized by suicidal and self-harming youth as a medium to communicate with and to seek social support from other users. Online social networking also leads to increased exposure to and engagement in self-harm behavior due to users receiving negative messages promoting self-harm, emulating self-injurious behavior of others, and adopting self-harm practices from shared videos. Greater time spent on social networking websites led to higher psychological distress, an unmet need for mental health support, poor self-rated mental health, and increased suicidal ideation. In conclusion, greater time spent on online social networking promotes self-harm behavior and suicidal ideation in vulnerable adolescents.


Iron oxide nanoparticle encapsulated diatoms for magnetic delivery of small molecules to tumors.
Small molecules can be co-loaded with iron oxide nanoparticles onto diatoms. With an external magnetic field, the diatoms, after systemic administration, can be attracted to tumors. This study suggests a great potential of diatoms as a novel and powerful therapeutic vehicle.


Influence of colour Doppler echocardiography on the ultrasonic assessment of congenital heart disease: a prospective study.
To evaluate the additional information provided by colour Doppler in the ultrasonic assessment of congenital heart disease. A prospective study of 215 children (age range 1 day-16 years) presenting with clinical signs of congenital heart disease. Colour Doppler was essential for the diagnosis of an anomalous left coronary artery and altered the management of a patient initially diagnosed as having cardiomyopathy. Colour Doppler provided extra information, but without major impact on management, in the following: the diagnosis of ventricular septal defects associated with other defects, of multiple ventricular septal defects, of anomalous pulmonary venous drainage, and of mild mitral regurgitation; the demonstration of site of coarctation, of stenotic or hypoplastic pulmonary artery branches, of unobstructed flow through a right atrial membrane, and of left ventricle to right atrium regurgitation; the assessment of the width of the duct and of flow through the patent foramen ovale in transposition and tricuspid atresia; the differentiation of pulmonary atresia from critical pulmonary stenosis and the measurement of maximum velocity of tricuspid regurgitation. Ideally all patients should undergo colour Doppler studies before cardiac surgery to ensure a more accurate diagnosis. However, since the additional information provided does not affect the management in most patients, machines without colour Doppler can provide a satisfactory service in paediatric cardiology centres in countries where resources are limited.


The management of acute venous thromboembolism in clinical practice. Results from the European PREFER in VTE Registry.
Venous thromboembolism (VTE) is a significant cause of morbidity and mortality in Europe. Data from real-world registries are necessary, as clinical trials do not represent the full spectrum of VTE patients seen in clinical practice. We aimed to document the epidemiology, management and outcomes of VTE using data from a large, observational database. PREFER in VTE was an international, non-interventional disease registry conducted between January 2013 and July 2015 in primary and secondary care across seven European countries. Consecutive patients with acute VTE were documented and followed up over 12 months. PREFER in VTE included 3,455 patients with a mean age of 60.8 ± 17.0 years. Overall, 53.0 % were male. The majority of patients were assessed in the hospital setting as inpatients or outpatients (78.5 %). The diagnosis was deep-vein thrombosis (DVT) in 59.5 % and pulmonary embolism (PE) in 40.5 %. The most common comorbidities were the various types of cardiovascular disease (excluding hypertension; 45.5 %), hypertension (42.3 %) and dyslipidaemia (21.1 %). Following the index VTE, a large proportion of patients received initial therapy with heparin (73.2 %), almost half received a vitamin K antagonist (48.7 %) and nearly a quarter received a DOAC (24.5 %). Almost a quarter of all presentations were for recurrent VTE, with >80 % of previous episodes having occurred more than 12 months prior to baseline. In conclusion, PREFER in VTE has provided contemporary insights into VTE patients and their real-world management, including their baseline characteristics, risk factors, disease history, symptoms and signs, initial therapy and outcomes.


Local climate change cultures: climate-relevant discursive practices in three emerging economies.
In recent decades, greater acknowledgement has been given to climate change as a cultural phenomenon. This paper takes a cultural lens to the topic of climate change, in which climate-relevant understandings are grounded in wider cultural, political and material contexts. We approach climate-relevant accounts at the level of the everyday, understood as a theoretically problematic and politically contested space This is in contrast to simply being the backdrop to mundane, repetitive actions contributing to environmental degradation and the site of mitigative actions. Taking discourse as a form of practice in which fragments of cultural knowledge are drawn on to construct our environmental problems, we investigate citizens' accounts of climate-relevant issues in three culturally diverse emerging economies: Brazil, South Africa and China. These settings are important because greenhouse gas (GHG) emissions are predicted to significantly increase in these countries in the future. We conducted semi-structured interviews with a range of citizens in each country using a narrative approach to contextualise climate-relevant issues as part of people's lifestyle narratives. Participants overwhelmingly framed their accounts in the context of locally-salient issues, and few accounts explicitly referred to the phenomenon of climate change. Instead, elements of climate changes were conflated with other environmental issues and related to a wide range of cultural assumptions that influenced understandings and implied particular ways of responding to environmental problems. We conclude that climate change scholars should address locally relevant understandings and develop dialogues that can wider meanings that construct climate-relevant issues in vernacular ways at the local level.


[Endocrine cells in gastric carcinoma].
A few endocrine cells were observed in 7 of 16 specimens of gastric carcinoma studied by electronmicroscopy. They were closely mixed with other types of tumor cells infiltrating into the stroma. Some endocrine cells contained both neuroendocrine and mucous granules. This conforms well to the hypothesis that the endocrine cells as well as other types of tumor cells in gastric carcinoma, originate from the endoderm. The endocrine cells and other varieties of tumor cells were found in both intestinal and diffuse types of gastric carcinoma. The heterogeneity and histogenesis of gastric carcinoma are discussed.


PDGF-BB and bFGF ameliorate radiation-induced intestinal progenitor/stem cell apoptosis via Akt/p53 signaling in mice.
Radiation-induced gastrointestinal (GI) syndrome currently has no effective prophylactic or therapeutic treatment. Previous studies and our data have demonstrated the important role of p53 in acute radiation-induced GI syndrome in mice. Many cytokines, such as tumor necrosis factor-α and fibroblast growth factor (bFGF), have been found to protect against radiation-induced intestinal injury, although the underlying mechanisms remain to be identified. Here, we report blockage of p53 through a protein kinase B (Akt) pathway in intestinal progenitor/stem cells or crypt cells as a novel molecular mechanism of growth factor-mediated intestinal radioprotection. Treatment with platelet-derived growth factor (PDGF-BB) or bFGF activated Akt phosphorylation in the intestinal crypt, lessened intestinal crypt p53 expression, decreased radiation-induced apoptosis in mouse intestinal progenitor/stem cell marker leucine-rich repeat-containing G protein-coupled receptor 5 (Lgr5)-positive cells by an average of 50%, and increased the survival rate of mice with abdominal radiation by 3 days in average. Conversely, the Akt inhibitor perifosine obstructed growth factor-simulated Akt phosphorylation while promoting radiation-induced p53 expression in intestinal crypts. Importantly, reduced Akt phosphorylation and elevated p53 expression due to the Akt inhibitor perifosine impaired intestinal progenitor/stem cells radioprotection provided by PDGF-BB and bFGF. Consistently, PDGF-BB and bFGF both upregulated Akt activation, suppressed radiation-induced p53 expression, and abrogated radiation-induced apoptosis in IEC-6 cells, although p53 overexpression in IEC-6 cells partially counteracted the radioprotection of PDGF-BB and bFGF. Our data suggest that intestinal crypt radioprotection by PDGF-BB and bFGF is dependent on regulation of Akt/p53 signaling.


Symptomatic and physiologic outcomes one year after peroral esophageal myotomy (POEM) for treatment of achalasia.
Peroral esophageal myotomy (POEM) is a new endoscopic operation for the treatment of achalasia. Here, we report 1-year physiologic and symptomatic outcomes following the procedure. POEM patients from a single-institution series who were more than 1 year removed from surgery were studied. Eckardt and GerdQ scores were obtained to assess symptoms. High-resolution manometry (HRM), timed barium esophagram (TBE), and upper endoscopy were preformed preoperatively and at 1-year follow-up. 24-h pH monitoring was also performed at 1 year follow-up. The study population was comprised of 41 patients who were more than 1 year post-POEM. One (2%) major complication, a contained leak at the EGJ requiring re-operation, and 7 (17%) minor complications occurred. Mean length of stay was 1.4 days. At mean 15-month follow-up, Eckardt scores improved from pre-POEM 7 ± 2 to post-POEM 1 ± 2, (scale 0-12, p < .001), and 92% of patients achieved treatment success (Eckardt score <4). Two of the three treatment failures in the series occurred in the initial three patients. 15% of patients had post-POEM symptoms suggestive of gastroesophageal reflux (GerdQ >7). On follow-up HRM, esophagogastric junction integrated relaxation pressure was decreased significantly (pre-POEM 28 ± 12 mmHg vs. post-POEM 11 ± 4 mmHg, p < .001), and 47% of patients studied had partial recovery of peristalsis. On follow-up TBE, barium column heights were decreased compared with preoperatively. Postoperative upper endoscopy revealed esophagitis in 59% of patients (11 LA Grade A, 2 LA Grade D). However, of the 13 24-h pH monitoring studies performed, only four (31%) demonstrated pathologic esophageal acid exposure. In this series, POEM resulted in greater than 90% symptomatic treatment success at mean 15-month follow-up. Rates of iatrogenic gastroesophageal reflux, as measured both by symptoms and 24-h pH monitoring, appeared to be on par with recent studies of patients undergoing laparoscopic Heller myotomy and pneumatic dilation.


Variability maps of body surface ECG in normal subjects.
A method for quantifying the fluctuations of the QRS electrocardiogram over the flat (unrolled) thoracic surface in normal subjects is presented. Serial comparisons were performed on 32-lead ECG recordings and body surface maps from seven healthy men, using as similarity measures correlation and RMS-difference in both time-signal and 2D map domain. Recordings were made on one and the same day, and on different days. The time-signal correlation and RMS-differences were plotted as 2D distributions. Correlation was higher on the front of the torso and RMS-differences were largest in the precordial area. The average time-signal correlation calculated over the QRS in comparisons of signals taken on different days was 0.9717, whereas the corresponding RMS-difference was 57.8 microV. Additionally, 2D comparisons between reconstructed map frames at different time instants in the QRS were carried out, using the 2D versions of the correlation and RMS-difference. The averaged results of the 2D comparisons were close to the time-signal comparison values (respectively 0.9696 and 68.9 microV). Finally, 2D comparisons between isointegral maps (mapping the QRS signal integral) were performed. They yielded even higher correlations (0.98, 3.453 microV s). Although the number of subjects studied was not large, the investigation brought to light important variability ranges that may serve as a basis when detecting pathologies. In addition, the topology of normal ECG variability on the body surface was revealed. This study confirmed the pertinence of correlation and RMS-difference as measures of time-signal and map similarity.


Activated signal transducer and activator of transcription-3 (STAT3) is a poor regulator of tumour necrosis factor-alpha production by human monocytes.
Signal transducer and activator of transcription-3 (STAT3) activation has been associated with suppressed inflammatory processes in experimental animals, murine myeloid cells and macrophage cell lines. Manipulation of STAT3 activity may therefore be a focus for pharmacological intervention of inflammatory diseases in humans. However, the ability of STAT3 to reduce the production of inflammatory mediators by activated human monocytes and macrophages has been characterized inadequately. To establish this, we used a recently optimized adenoviral approach to study the effect of overexpressed STAT3 or a transcriptionally inactive mutant STAT3 in lipopolysaccharide (LPS)-stimulated human monocytes. STAT3 activated by LPS did not directly regulate inhibitor of kappa B alpha (IkappaBalpha) activation or tumour necrosis factor (TNF)-alpha production, a process dependent on the transcriptional activity of nuclear factor kappa B (NFkappaB), although the transcriptional activity of STAT3 contributed to the mechanism by which interleukin (IL)-10 suppressed LPS-induced TNF-alpha levels. This contrasted with the efficient block in IL-10 induction of suppressor of cytokine signalling-3 (SOCS3) in monocytes infected with an adenovirus expressing mutant STAT3. These results indicate that STAT3 activation cannot directly regulate LPS-signalling in human monocytes and represents only part of the mechanism by which IL-10 suppresses TNF-alpha production by activated human monocytes. This study concludes that pharmacological manipulation of STAT3 transcriptional activity alone would be insufficient to control NFkappaB-associated inflammation in humans.


How to Regulate the Right to Self-Medicate.
In Pharmaceutical Freedom Professor Flanigan argues we ought to grant people self-medication rights for the same reasons we respect people's right to give (or refuse to give) informed consent to treatment. Despite being the most comprehensive argument in favour of self-medication written to date, Flanigan's Pharmaceutical Freedom leaves a number of questions unanswered, making it unclear how the safe-guards Flanigan incorporates to protect people from harming themselves would work in practice. In this paper, I extend Professor Flanigan's account by discussing a hypothetical case to illustrate how these safe-guards could work together to protect people from harms caused by their own ignorance or incompetence.


Rheumatic manifestations in brazilian patients with AIDS.
Patients with AIDS (acquired immunodeficiency syndrome) may have rheumatic complaints such as arthritis and arthralgia, dry eyes, increased salivary glands, lower back pain, enthesitis etc. Autoantibodies like ANA (antinuclear antibody) and RF (rheumatoid factor) may also be present. To study the prevalence of rheumatic complaints in AIDS patients and correlate them with the presence of ANA and RF. We studied 69 patients with AIDS (28.9% women and 71.0% men) with a mean age of 40.8 ± 8.9 years, median disease duration of 60 months, for rheumatic complaints, ANA, ENA-6 (anti-Ro, anti-La, anti-Sm, anti-RNP, anti-Scl70 and anti-Jo1) and RF. We collected demographic data, CD4+ and CD8+ cell count and values of viral load. Arthralgia was present in 39.1%, sicca symptoms in 21.7%, inflammatory lumbar pain in 13.4%, enthesopathy in 6.6%, parotid enlargement in 1.4%, RF in 10.1% and ANA in 8.6%. All patients were negative for ENA-6. ANA was more common in older patients (p = 0.03) and in those with higher viral load (p = 0.006). No association was found with the presence of RF. The most common manifestation in this context was arthralgia. ANA presence was associated with age of the patients and viral load.


The emotional impact of the COVID-19 pandemic on individuals with progressive multiple sclerosis.
Individuals with pre-existing chronic illness have shown increased anxiety and depression due to COVID-19. Here, we examine the impact of the COVID-19 pandemic on emotional symptomatology and quality of life in individuals with Progressive Multiple Sclerosis (PMS). Data were obtained during a randomized clinical trial on rehabilitation taking place at 11 centers in North America and Europe. Participants included 131 individuals with PMS. Study procedures were interrupted in accordance with governmental restrictions as COVID-19 spread. During study closure, a COVID Impact Survey was administered via telephone or email to all participants, along with measures of depressive symptoms, anxiety symptoms, quality of life, and MS symptomatology that were previously administered pre-pandemic. 4% of respondents reported COVID-19 infection. No significant changes were noted in anxiety, quality of life, or the impact of MS symptomatology on daily life from baseline to lockdown. While total HADS-depression scores increased significantly at follow-up, this did not translate into more participants scoring above the HADS threshold for clinically significant depression. No significant relationships were noted between disease duration, processing speed ability or EDSS, and changes in symptoms of depression or anxiety. Most participants reported the impact of the virus on their psychological well-being, with a little impact on financial well-being. The perceived impact of the pandemic on physical and psychological well-being was correlated with the impact of MS symptomatology on daily life, as well as changes in depression. Overall, little change was noted in symptoms of depression or anxiety or overall quality of life.


Using the Tet-On system to develop a procedure for extracting transcription factor activation dynamics.
The regulation of gene expression by transcription factors through different expression and activation dynamics is an important aspect of genomics and systems biology. Reporter systems using green fluorescent protein (GFP) or luciferase are often used to infer transcription factor dynamics. We recently used an inverse problem solution of GFP reporter profiles to demonstrate that the activation dynamics of a model transcription actor (NF-kappaB) can be reconstructed from GFP data. This approach assumes that the general nature of the transcription factor dynamics is known; however, it is non-trivial to determine the exact nature of the transcription factor dynamics as it often depends upon the cell type and the stimulus used to activate the transcription factor. This, in turn, limits the determination of accurate transcription factor dynamics from reporter data, especially since the model used for solution of an inverse problem needs to be verified. To address this point, we developed a reporter cell line for expressing GFP using an inducible, artificial transcription factor (tTA) and minimal promoter system. The artificial transcription factor can be activated independent of the cellular regulatory machinery through addition of doxycycline. This allows us to directly control the dynamics of the artificial transcription factor, and thereby, develop a model describing its activation dynamics from reporter data. Our experimental data and model predictions are in good agreement, and illustrate the utility of our approach. Future work will focus on using the developed approach, i.e. solution of an inverse problem involving the model describing expression of GFP, to extract the dynamics of transcription factors that are currently uncharacterized.


Pathology of experimental Ebola virus infection in African green monkeys. Involvement of fibroblastic reticular cells.
Ebola virus has been responsible for explosive lethal outbreaks of hemorrhagic fever in both humans and nonhuman primates. Previous studies showed a predilection of Ebola virus for cells of the mononuclear phagocyte system and endothelial cells. To examine the distribution of lesions and Ebola virus antigen in the tissues of six adult male African green monkeys (Cercopithecus aethiops) that died 6 to 7 days after intraperitoneal inoculation of Ebola-Zaire (Mayinga) virus. Tissues were examined histologically, immunohistochemically, and ultrastructurally. A major novel finding of this study was that fibroblastic reticular cells were immunohistochemically and ultrastructurally identified as targets of Ebola virus infection. The role of Ebola virus-infected fibroblastic reticular cells in the pathogenesis of Ebola hemorrhagic fever warrants further investigation. This is especially important because of recent observations indicating that fibroblastic reticular cells, along with the reticular fibers they produce, maximize the efficiency of the immune response.


Clinical indications for computed tomographic colonography: European Society of Gastrointestinal Endoscopy (ESGE) and European Society of Gastrointestinal and Abdominal Radiology (ESGAR) Guideline.
This is an official guideline of the European Society of Gastrointestinal Endoscopy (ESGE) and the European Society of Gastrointestinal and Abdominal Radiology (ESGAR). It addresses the clinical indications for the use of computed tomographic colonography (CTC). A targeted literature search was performed to evaluate the evidence supporting the use of CTC. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was adopted to define the strength of recommendations and the quality of evidence. Main recommendations 1 ESGE/ESGAR recommend computed tomographic colonography (CTC) as the radiological examination of choice for the diagnosis of colorectal neoplasia. ESGE/ESGAR do not recommend barium enema in this setting (strong recommendation, high quality evidence). 2 ESGE/ESGAR recommend CTC, preferably the same or next day, if colonoscopy is incomplete. Delay of CTC should be considered following endoscopic resection. In the case of obstructing colorectal cancer, preoperative contrast-enhanced CTC may also allow location or staging of malignant lesions (strong recommendation, moderate quality evidence). 3 When endoscopy is contraindicated or not possible, ESGE/ESGAR recommend CTC as an acceptable and equally sensitive alternative for patients with symptoms suggestive of colorectal cancer (strong recommendation, high quality evidence). 4 ESGE/ESGAR recommend referral for endoscopic polypectomy in patients with at least one polyp ≥ 6 mm in diameter detected at CTC. CTC surveillance may be clinically considered if patients do not undergo polypectomy (strong recommendation, moderate quality evidence). 5 ESGE/ESGAR do not recommend CTC as a primary test for population screening or in individuals with a positive first-degree family history of colorectal cancer (CRC). However, it may be proposed as a CRC screening test on an individual basis providing the screenee is adequately informed about test characteristics, benefits, and risks (weak recommendation, moderate quality evidence).


Factors related to parental COVID-19 vaccine hesitancy for children: An exploratory factor analysis model.
This pandemic has been accompanied by an overabundance of information and misinformation, an 'infodemic' on a global scale which have made acceptability of COVID-19 vaccine a major challenge. The objective of the study was to find out the Beliefs of mothers towards COVID-19 vaccine for children and its impact on vaccine hesitancy. After obtaining Institutional ethical clearance and informed consent, a total of 360 mothers who were having at least one child from 5 to 18 years were recruited based on simple random sampling. Face-to-face interview was conducted. The questionnaire was based on the WHO-SAGE working group on vaccine hesitancy. Based on Bartlett's test of sphericity, the model was found to be fit (there is adequate number of correlations for factor analysis) and KMO test results imply the samples are adequate for factor analysis. K means cluster analysis was used to divide the samples into three clusters and individual respondent's cluster membership was also identified. It was found 49.4% of mothers were hesitant to vaccine their children against COVID-19. The seven items (reasons for vaccine hesitancy) were grouped into three dimensions (believes in vaccine effectiveness but concerned about side effects, believes in the importance of taking COVID vaccine, trusts information about COVID vaccine), based on how each item loads on to each of three factors. Cluster 1 was that they believe in effectiveness of vaccine but are concerned about side effects (.92094). Mothers' concerns were mainly about the safety and adverse effects of vaccine.


Littoral cell angioma of the spleen: an additional report of four cases with emphasis on the association with visceral organ cancers.
Littoral cell angioma (LCA) is an uncommon vascular tumor of the spleen recently described and interpreted as the tumoral counterpart of the normally present littoral cells lining the splenic sinus channels of red pulp. The diagnosis of LCA is suggested by a quite characteristic morphology and confirmed by the demonstration of a hybrid endothelial/histiocytic phenotype. Four original and previously unreported cases of LCA are presented. All four splenic vascular tumors were investigated by light microscopy and immunohistochemistry for endothelial and histiocytic markers. All four cases were associated with visceral epithelial malignancies (colorectal adenocarcinoma in two cases, renal and pancreatic adenocarcinoma in one case each). One case was also associated with an intracranial tentorial meningioma. We consider our findings as a novelty and signal the possible existence of a clinical syndrome. Five of a total of 21 previously reported cases in the literature were also described as being associated with other cancers (non-Hodgkin's lymphoma in two cases, two not further specified tumors of the liver and brain, an epithelial ovarian cancer, and a non-small cell lung cancer in one case each). Close follow-up and careful investigation in search of a second visceral neoplasm are strongly recommended in cases of LCA, but further clinical observations and more in-depth genetic and molecular studies are needed before any valid conclusions can be drawn.


Treatment outcomes of patients with classic and AIDS-related Kaposi Sarcoma: a single-center real-world experience.
The recommended first-line chemotherapy agents for managing Kaposi sarcoma (KS) in high-income countries are expensive and often unavailable in developing nations such as Peru. Limited data exist on whether management practices in these countries affect patient outcomes. We assessed the real-world treatment approaches and outcomes of patients with KS in Peru. We retrospectively reviewed the medical records of patients with acquired immunodeficiency syndrome-related KS (AIDS-related KS; n = 95) and classic KS (CKS; n = 81) diagnosed at a tertiary center between 2000 and 2014 in Lima, Peru. We used the Kaplan-Meier method to estimate overall survival (OS) rates. The median follow-up was 64 months for AIDS-related KS and 88 months for CKS. The median age of patients with AIDS-related KS was 35 years (range 20-63 years) and 70 years (range 33-91 years) for those with CKS. Most individuals had an Eastern Cooperative Oncology Group performance status of ≥ 2 (AIDS-related KS 75%; CKS 85%). Seventy-six percent and 40% of individuals with AIDS-related KS and CKS, respectively, received systemic chemotherapy. The most common first-line drug was paclitaxel, with relatively optimal overall response rates (ORRs) for AIDS-related KS (n = 64/72, 89%; ORR 61%) and CKS (n = 24/32, 75%; ORR 50%). The 5-year OS rates were 71% in the AIDS-related KS cohort and 81% in the CKS cohort. The findings from this real-world study may inform clinical practices and highlight the need for increased access to effective treatments and clinical trials for patients with KS in Peru and other developing countries.


Vitamin D: a growing perspective.
Vitamin D deficiency has been widely reported in all age groups in recent years. Rickets has never been eradicated in developed countries, and it most commonly affects children from recent immigrant groups. There is much evidence that current vitamin D guidelines for the neonatal period, 5-10 microg (200-400 IU)/day, prevent rickets at the typical calcium intakes in developed countries. The annual incidence of vitamin D-deficiency rickets in developed countries ranges between 2.9 and 7.5 cases per 100,000 children. The prevalence of vitamin D deficiency in mothers and their neonates is remarkable, and the results of one study suggest that third-trimester 25-hydroxyvitamin D (25(OH)D) is associated with fetal bone mineral accrual that may affect prepubertal bone mass accumulation. Beyond infancy, the evidence indicates that 5 microg (200 IU)/day of vitamin D has little effect on vitamin D status as measured by the serum 25(OH)D concentration. Two randomized clinical trials show that higher vitamin D intake improves one-year gain in bone density in adolescent girls. The functions of vitamin D extend beyond bone to include immune system regulation and anti-proliferative effects on cells. Early life vitamin D inadequacy is implicated in the risk of bone disease, autoimmune disease, and certain cancers later in life; however, long-term interventional studies do not exist to validate the widespread implementation of greater vitamin D consumption. Here we review the available data concerning vitamin D status and health effects of vitamin D in pregnancy through to and including adolescence.


Research ethics and private harms.
This commentary addresses the emotionally powerful account of Nicole Taus Kluemper from the perspective of a psychologist familiar with the administrative operation of the American Psychological Association (APA) and the ethics of the profession. The application of the APA's Ethical Principles of Psychologists and Code of Conduct to the case is discussed, and alternative methods of response that researchers who have concerns about case studies might use are offered. The author concludes that existing ethical principles-the aspirational standards in particular-do bear upon the matter in question. However, the enforceable code of conduct is not sufficiently clear about obligations to those whom psychologists publicly discuss when the psychologist does not have a specific duty of care to an individual.


The actions of FMRF-NH2 and FMRF-NH2 related peptides on mammals.
Since the initial isolation and characterization of FMRFamide (Phe-Met-Arg-Phe-NH2) from a molluscan source, the potential for the interaction of this neuropeptide with opioid systems has been suspected. Immunoreactive FMRFamide-like material is found in mammals (particularly in brain, spinal cord and GI tract) and mammalian-derived FMRFamide-related peptides (FaRPs) have been identified. A considerable amount of data supports the hypothesis that FMRFamide or mammalian FaRPs function as endogenous antiopiates, particularly with regard to opioid-induced antinociception and other opioid-induced behaviors. They have also been reported to be capable of altering the rate of morphine tolerance development and precipitating withdrawal in morphine-dependent animals. These data imply that FMRFamide or FaRPs are competitive antagonists at opiate receptors. The relatively low affinity for opiate receptors also suggests other possibilities, including mammalian FMRFamide (or FaRP) receptors equivalent to those in invertebrates, partial agonism at opiate receptors or, an indirect (modulatory) role. Whatever the actual mechanism, FMRFamide-like peptides and other 'anti-opiate' peptides might have critical roles in the development of opioid tolerance and dependence or in the pharmacologic study or clinical treatment of these phenomena.


A Critical Appraisal of Vascularized Bone Grafting for Scaphoid Nonunion.
Background Vascularized bone grafting (VBG) has the potential to yield reliable results in scaphoid nonunion; however, results across studies have been highly variable. This study critically evaluates surgical techniques, fracture location, and patient selection in relation to radiographic, clinical, and patient-centered outcomes after VBG for scaphoid nonunion. Methods We conducted a systematic review of the literature for the use of VBG in scaphoid nonunion. Physical examination, radiographic, and patient-centered outcomes were assessed. Four substratifications were performed: the location of scaphoid nonunion, pedicled versus free technique, Kirschner wire (K-wire) versus screw fixation, and VBG done as a primary versus revision procedure. Results A total of 41 publications were included in final analysis. VBG had an 84.7% union rate at 13 weeks after surgery. On an average, 89% of patients returned to preinjury activity levels by 18 weeks after surgery and 91% of patients reported satisfaction with the procedure. Proximal pole nonunions demonstrated similar union rates but lower functionality scores compared with nonunions across all regions of the scaphoid. Pedicled techniques demonstrated slightly improved range of motion compared with free technique. K-wire versus screw fixation demonstrated significantly higher union rates and faster union times. There were no differences in outcomes for VBG done as a primary versus revision procedure. Conclusion VBG serves as a viable option for the treatment of scaphoid nonunion, with consistent union rates in addition to significantly improved postoperative patient functionality. The fixation of these vascularized bone grafts with K-wires versus screw fixation may result in superior radiologic outcomes. Level of Evidence Therapeutic, Level III, systematic review.


Intramuscularly injected neurotropin reduced muscular mechanical hyperalgesia induced by repeated cold stress in rats.
An extract of rabbit skin inflamed by inoculation with the vaccinia virus, neurotropin [by intravenous, oral, and intramuscular (i.m.) administration], has been used in China and Japan for the treatment of chronic pain. In this study, we investigated the analgesic mechanism of i.m. neurotropin. Rats were exposed to repeated cold stress, and muscular mechanical hyperalgesia was evaluated by measuring the withdrawal threshold of the gastrocnemius muscle using Randall-Selitto apparatus. I.m. but not subcutaneous, neurotropin dose dependently reduced the repeated cold stress-induced muscular mechanical hyperalgesia for 3 h, but it had no effect in normal rats. Injections of neurotropin into the right gastrocnemius, quadriceps femoris, biceps brachii, and trapezius muscles reduced the muscular mechanical hyperalgesia of the gastrocnemius muscle bilaterally. Intrathecal administration of antagonists to GABAergic, serotonergic, and cholinergic receptors, but not α2-adrenergic receptors, and intraperitoneal administration of opioid receptor antagonist inhibited the analgesic effect of neurotropin. These results indicated that an i.m. injection of neurotropin induced long-lasting wide-spread bilateral muscular analgesia by activating spinal serotonergic and GABAergic receptors. As distinct from analgesia by systemic administration, spinal cholinergic and opioidergic, but not adrenergic receptors, are also involved. The present study supports the effectiveness of neurotropin treatment for muscular mechanical hyperalgesia.


[Ultraviolet: a regulator of immunity].
Humans establish acquired immune systems during the growth, which can sufficiently eliminate pathogen avoiding immune responses to self, such as allergy and autoimmunity. An imbalance of the acquired immune system leads up to immune-mediated disorders. Ultraviolet (UV) exposure helps to establish the normal peripheral tolerance to contact allergen avoiding excessive immune responses. By contrast, UV develops kinds of autoimmune diseases on rare occasions, suggesting that abnormality in the process of UV-induced peripheral tolerance may induce these diseases. To elucidate the mechanism of UV-induced tolerance is possible to provide a new approach for the management of immune diseases. In the current review, focus is on the suggested players of UV-induced tolerance, blocking mechanisms on the elicitation phase of contact hypersensitivity, and the association between UV and autoimmunity. The major impact in basic immunology in this area is the discovery of cell surface marker of regulatory T cells. Therefore, we first discuss about the association of regulatory/suppressor T cells with UV-induced tolerance. Since the elicitation phase depends on cellular influx into the inflammatory sites, which is tightly regulated by adhesion molecules, we also focused on the role of adhesion molecules. Finally, this paper also includes statistical findings concerning the association between UV-radiation and the prevalence of a myositis specific autoantibody. Thus, UV is one of the nice regulators of an immune network and the knowledge of UV-mediated immune regulation will be translated into new therapeutic strategies to human immune-mediated disorders.


Cognitive reactivity, dysfunctional attitudes, and depressive relapse and recurrence in cognitive therapy responders.
Dysfunctional attitudes can foreshadow depressive relapse/recurrence. Priming mood, through induction paradigms, is hypothesized to activate dysfunctional attitudes. Cognitive reactivity (CR) refers to mood-linked increases in dysfunctional attitudes after priming. Here we explored the extent to which CR as well as residual, unprimed, dysfunctional attitudes predicted depressive relapse/recurrence among depressed patients who responded to acute phase cognitive therapy (CT). Consenting adults, aged 18-70, with recurrent major depressive disorder (n = 523) participated in a two-site randomized controlled trial examining the durability of continuation phase treatments. Patients received 16-20 sessions of CT. Among the 245 incompletely remitted responders, 213 agreed to undergo a mood induction paradigm. After 8 months of continuation phase treatments, participants were followed an additional 24 months. Although the mood induction significantly lowered mood in 80% of responders, the expected CR was not evident. By contrast, higher unprimed dysfunctional attitudes following CT did predict relapse/recurrence over 20 and 32 months post-randomization. The findings of this large longitudinal study of incompletely remitted CT responders challenge the notion that it is necessary to prime mood in order to maximize dysfunctional attitudes' prediction of relapse and/or recurrence. While findings cannot be generalized beyond CT responders, they emphasize the clinical importance of reducing dysfunctional attitudes in preventing depression.


Synthesis and Antimicrobial Evaluation of New Cephalosporin Derivatives Containing Cyclic Disulfide Moieties.
Due to a steady increase in microbial resistance, there is a need to increase the effectiveness of antibiotic performance by involving additional mechanisms of their penetration or retention for their better action. Cephalosporins are a successful group of antibiotics to combat pathogenic microorganisms, including drug-resistant strains. In this study, we investigated the effect of newly synthesized cephalosporin derivatives with cyclic disulfide modifications against several Gram-positive and Gram-negative strains as well as against biofilm formation. The incorporation of asparagusic acid was found to be effective in improving the activity of the drug against Gram-negative strains compared to the all carbon-control compounds. Furthermore, we could demonstrate the successful reduction of biofilm formation for Staphylococcus aureus and Pseudomonas aeruginosa at similar concentrations as obtained against planktonic cells. We propose that the incorporation of cyclic disulfides is one additional strategy to improve antibiotic activity and to combat bacterial infections.


Stability study of concentrate-solvent mixture & infusion solutions of Jevtana® cabazitaxel for extended multi-dosing.
In this study, the prolonged physical and chemical stability of the anticancer agent cabazitaxel, commercially available as Jevtana®, was examined. Both concentrate-solvent mixture and infusion solution were examined with the aim to extend the use of multidose left-over cabazitaxel and infusion solutions and with that reduce financial and environmental waste. A validated stability-indicating high-pressure liquid chromatography (HPLC) method with ultraviolet (UV) and photodiode array (PDA) detection was used to examine the purity and any degradation of cabazitaxel. The concentrate-solvent mixture and infusion solution samples that were tested had been stored out of the range of the criteria stated in the summary of product characteristics (SmPC). The concentrate-solvent mixtures were stored at 3-5°C, 18-21°C, and 40 °C, whereas the infusion solution was stored at 3-5°C. All samples were tested at t = 0, t = 1 week and t = 2 weeks. All samples showed that purity and concentration had remained within the criteria of <5% as stated in the European Pharmacopoeia. However, the concentrate-solvent mixtures stored at 18-21°C and 40 °C showed a degradation product forming in all the samples lowering the purity of the samples from 100% to 99.91% and 98.20% respectively, whereas all samples stored at 3-5°C remained at 100%. Concentrate-solvent mixture and infusion solution of cabazitaxel, Jevtana®, can be used up to 2 weeks after preparation if stored at 3-5°C and prepared under aseptic conditions.


Long-term estradiol treatment improves VIP-mediated vasodilation in atherosclerotic proximal coronary arteries.
The aim of the present study was to evaluate the impact of long-term estrogen replacement therapy (ERT) on the vasodilatory effect of the two peptides vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) in atherosclerotic coronary and cerebral arteries. Female ovariectomized homozygous Watanabe heritable hyperlipidemic rabbits were randomized to 16 weeks treatment with 17beta-estradiol or placebo. The diet was semisynthetic, thereby avoiding the influence of phytoestrogens. Artery ring segments were mounted for isometric tension recordings in myographs. Following precontraction, the dose-response relationships for VIP and PACAP were evaluated.Treatment with 17beta-estradiol significantly improved the maximum VIP-mediated vasodilation (E(max), percentage of precontraction) in proximal coronary arteries (45.8+/-9.6% vs. 24.1+/-3.7%, p<0.05). In the same artery segment, 17beta-estradiol induced a significant decrease in the relative ratio between the repeated contractile response to potassium 30 and 120 mM (100+/-7% vs. 132+/-11%, p<0.05). For distal coronary arteries, there was a tendency to similar changes, but no statistical differences for the potassium or VIP responses in cerebral or distal coronary arteries were found between the two groups. 17beta-estradiol induced no changes in the PACAP-mediated vasodilation. These results suggest that long-term treatment with 17beta-estradiol improves the VIP-mediated but not the PACAP-mediated vasodilation in atherosclerotic proximal coronary arteries.


Fungal melanin as a biocompatible broad-spectrum sunscreen with high antioxidant activity.
Melanin is considered a bio-inspired dermo-cosmetic component due to its high UV absorption and antioxidant activity. Among various melanin sources, fungal melanin is a promising candidate for sunscreen because of its sustainability and scalability; however, quantitative assessment of its function has not yet been sufficiently explored. In this study, melanin samples derived from Amorphotheca resinae were prepared, followed by the evaluation of their sunscreen performance, antioxidant activity, and cytotoxicity. Melanin-blended cream was prepared by blending a melanin suspension and a pure cream. The cream showed an in vitro sun protection factor value of 2.5 when the pigment content was 5%. The cream showed a critical wavelength of approximately 388 nm and a UVA/UVB ratio of more than 0.81, satisfying the broad-spectrum sunscreen requirement. Oxygen radical absorbance capacity assays indicated that fungal melanin had antioxidant activity similar to ascorbic acid but higher than reduced glutathione. Fungal melanin had no statistically significant cytotoxicity to human keratinocyte cell lines until 72 h of exposure, even at a concentration of 4 mg mL-1. Consequently, melanin pigment can be used as a biocompatible broad-spectrum sunscreen with high antioxidant activity and as a practical alternative in dermo-cosmetic formulations.


Pretreatment DST and hypothalamic-pituitary-adrenocortical function in depressed patients and comparison groups. A multicenter study.
Pretreatment measures of hypothalamic-pituitary-adrenocortical (HYPAC) function in depressed, manic, and healthy normal subjects showed that nonsuppression on the dexamethasone suppression test (DST) had less positive predictive value for major diagnostic category and was more frequent in normals (8/77) than recently reported, although it was yet more frequent in depressed patients (35/111). Nonsuppression was common in manics (8/16), was similar in unipolar and bipolar depressed patients (35% and 27%, respectively), and did not segregate with melancholic, endogenous, or psychotic depression subtypes. Patterns of post-DST plasma cortisol concentration other than simple escape or nonescape from suppression were common. Nonsuppression of 9 AM plasma cortisol levels on the DST had as good or better diagnostic specificity as nonsuppression of any of three post-DST samples. Nonsuppression was not completely synonymous with HYPAC hypersecretion. Means of pre-DST HYPAC measures (morning plasma cortisol, urine free cortisol, and CSF cortisol levels) were elevated in depressed patients compared with normals. There were significant differences in HYPAC measures of depressed patients studied at different centers. Age correlated positively and body weight negatively with plasma cortisol level.


BP75, bromodomain-containing M(r) 75,000 protein, binds dishevelled-1 and enhances Wnt signaling by inactivating glycogen synthase kinase-3 beta.
To identify novel regulators of Wnt signaling, we performed yeast two-hybrid analyses with Dvl-1 and identified BP75 as a candidate. Here, we demonstrated that BP75 directly interacts with Dvl-1 in mammalian cells and enhances TCF-dependent gene expression induced by Dvl-1. In support of these results, BP75 in cooperation with Dvl-1 was found to facilitate dephosphorylation at Tyr216 of glycogen synthase kinase-3beta and consequently inhibit its kinase activity. Furthermore, the nuclear translocation and formation of vesicular structures of beta-catenin were induced by BP75 and Dvl-1 in a synergistic manner. Collectively, these results provided us a novel mechanism in Wnt signaling where BP75 plays important regulatory roles between glycogen synthase kinase-3beta and Dvl.


The relationship between use of oral contraceptives and myocardial infarction in young women with fatal outcome, compared to those who survive: results from the MICA case-control study.
To examine the relationship between use of oral contraceptives and the risk of dying from myocardial infarction, we made a comparison of deceased patients and live patients (women aged less than 45) identified for the Myocardial Infarction Causality case-control study, using data obtained from general practice medical notes. There were 422 live patients and 110 deceased patients of women with a myocardial infarction with data available. The adjusted odds ratio for exposure to second generation oral contraceptives and risk of death within 28 days of a myocardial infarction compared with no oral contraceptive use was raised (2.88, 95% confidence interval 1.22-6.77), and this effect was not seen for other types of oral contraceptives including third generation oral contraceptive formulations. In absolute terms, between 47,000 and 71,000 women would have to be exposed to a second generation pill for one year to result in one extra death from myocardial infarction, and this risk applies mainly to smokers. The results suggest a slightly increased relative risk of death among those having a myocardial infarction associated with exposure to second generation oral contraceptives, but this represents a small absolute risk. Further work is required before any change in contraceptive practice should be advocated.


Extracellular synaptic factors induce clustering of acetylcholine receptors stably expressed in fibroblasts.
The clustering of nicotinic acetylcholine receptors (AChRs) is one of the first events observed during formation of the neuromuscular junction. To determine the mechanism involved in AChR clustering, we established a nonmuscle cell line (mouse fibroblast L cells) that stably expresses just one muscle-specific gene product, the AChR. We have shown that when Torpedo californica AChRs are expressed in fibroblasts, their immunological, biochemical, and electrophysiological properties all indicate that fully functional cell surface AChRs are produced. In the present study, the cell surface distribution and stability of Torpedo AChRs expressed in fibroblasts (AChR-fibroblasts) were analyzed and shown to be similar to nonclustered AChRs expressed in muscle cells. AChR-fibroblasts incubated with antibodies directed against the AChR induced the formation of small AChR microclusters (less than 0.5 micron 2) and caused an increase in the internalization rate and degradation of surface AChRs (antigenic modulation) in a manner similar to that observed in muscle cells. Two disparate sources of AChR clustering factors, extracellular matrix isolated from Torpedo electric organ and conditioned media from a rodent neuroblastoma-glioma hybrid cell line, each induced large (1-3 microns 2), stable AChR clusters with no change in the level of surface AChR expression. By exploiting the temperature-sensitive nature of Torpedo AChR assembly, we were able to demonstrate that factor-induced clusters were produced by mobilization of preexisting surface AChRs, not by directed insertion of newly synthesized AChRs. AChR clusters were never observed in the absence of extracellular synaptic factors. Our results suggest that these factors can interact directly with the AChR.


Effect of sportswear on performance and physiological heat strain during prolonged running in moderately hot conditions.
This study examined the impact of different upper-torso sportswear technologies on the performance and physiological heat strain of well-trained and national-level athletes during prolonged running in moderately hot conditions. A randomized crossover design was employed in which 20 well-trained (n = 16) and national-level (n = 4) athletes completed four experimental trials in moderately hot conditions (35°C, 30% relative humidity). In each trial, participants ran at 70% of their peak oxygen uptake (70% V̇O2peak ) for 60 min, while wearing a different upper-body garment: cotton t-shirt, t-shirt with sweat-wicking fabric, compression t-shirt, and t-shirt with aluminum dots lining the inside of the upper back of the garment. Running speed was adjusted to elicit the predetermined oxygen consumption associated with 70% V̇O2peak . Physiological (core and skin temperatures, total body water loss, and urine specific gravity) and perceptual (thermal comfort and sensation, ratings of perceived exertion, and garment cooling functionality) parameters along with running speed at 70% V̇O2peak were continuously recorded. No significant differences were observed between the four garments for running speed at 70% V̇O2peak , physiological heat strain, and perceptual responses (all p > 0.05). The tested athletes reported larger areas of perceived suboptimal cooling functionality in the cotton t-shirt and the t-shirt with aluminum dots relative to the sweat-wicking and compression t-shirts (d: 0.43-0.52). There were not differences among the tested garments regarding running speed at 70% V̇O2peak , physiological heat strain, and perceptual responses in well-trained and national-level endurance athletes exercising in moderate heat.


Vasopressin increases cytosolic free calcium concentration in glomerular mesangial cells.
Cytosolic free calcium concentration ([Ca2+]f) was determined in cultured rat glomerular mesangial cells under basal conditions and after exposure to arginine vasopressin (AVP) or angiotensin II (ANG II). [Ca2+]f was determined using quin 2 or fura-2, two intracellular fluorescent probes. [Ca2+]f was measured to be 102 +/- 3 nM (n = 154) using quin 2 and 82 +/- 4 (n = 34) using fura-2. AVP and ANG II increased [Ca2+]f. Maximal levels of [Ca2+]f were achieved in less than 10 s after addition of the hormone. This peak value was followed by a rapid fall toward the base line. With fura-2 as the intracellular Ca2+ indicator, [Ca2+]f increased from 74 +/- 7 to a peak of 578 +/- 39 nM (n = 17) with 100 nM AVP. At 115 s after addition of AVP, [Ca2+]f was 125 +/- 9 nM. Similar peak levels of [Ca2+]f were observed using quin 2. The increase in [Ca2+]f was due in large part to release of Ca2+ from intracellular stores, since reduction in extracellular free [Ca2+] with EGTA did not prevent the hormone-induced increase in [Ca2+]f, although it did result in a decreased peak level and a more rapid return to base line. The AVP-induced increase in [Ca2+]f was blocked by the V1 receptor antagonist (CH2)5Tyr(Me)VDAVP. Neither isoproterenol, which increased adenylate cyclase activity, nor dibutyryl cAMP had any affect on [Ca2+]f directly or on the AVP-induced increase in [Ca2+]f. In this report we present the first direct measurements of [Ca2+]f and hormone-induced changes in [Ca2+]f in glomerular mesangial cells.(ABSTRACT TRUNCATED AT 250 WORDS)